Publications by authors named "Gilles Simard"

73 Publications

Tear metabolomics highlights new potential biomarkers for differentiating between Sjögren's syndrome and other causes of dry eye.

Ocul Surf 2021 Jul 28;22:110-116. Epub 2021 Jul 28.

Mitolab, MitoVasc Institute, CNRS, 6015, INSERM U1083, University of Angers, France; Department of Biochemistry and Molecular Biology, University Hospital, Angers, France.

Purpose: The lacrimal exocrinopathy of primary Sjögren's syndrome (pSS) is one of the main causes of severe dry eye syndrome and a burden for patients. Early recognition and treatment could prevent irreversible damage to lacrimal glands. The aim of this study was to find biomarkers in tears, using metabolomics and data mining approaches, in patients with newly-diagnosed pSS compared to other causes of dry eye syndrome.

Methods: A prospective cohort of 40 pSS and 40 non-pSS Sicca patients with dryness was explored through a standardized targeted metabolomic approach using liquid chromatography coupled with mass spectrometry. A metabolomic signature predictive of the pSS status was sought out using linear (logistic regression with elastic-net regularization) and non-linear (random forests) machine learning architectures, after splitting the studied population into training, validation and test sets.

Results: Among the 104 metabolites accurately measured in tears, we identified a discriminant signature composed of nine metabolites (two amino acids: serine, aspartate; one biogenic amine: dopamine; six lipids: Lysophosphatidylcholine C16:1, C18:1, C18:2, sphingomyelin C16:0 and C22:3, and the phoshatidylcholine diacyl PCaa C42:4), with robust performances (ROC-AUC = 0.83) for predicting the pSS status. Adjustment for age, sex and anti-SSA antibodies did not disrupt the link between the metabolomic signature and the pSS status. The non-lipidic components also remained specific for pSS regardless of the dryness severity.

Conclusion: Our results reveal a metabolomic signature for tears that distinguishes pSS from other dry eye syndromes and further highlight nine key metabolites of potential interest for early diagnosis and therapeutics of pSS.
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http://dx.doi.org/10.1016/j.jtos.2021.07.006DOI Listing
July 2021

Preliminary Metabolomic Profiling of the Vitreous Humor from Hypothermia Fatalities.

J Proteome Res 2021 05 5;20(5):2390-2396. Epub 2021 Apr 5.

Centre Universitaire Romand de Médecine Légale, Hôpital Universitaire de Lausanne, 1000 Lausanne 25, Switzerland.

The postmortem diagnosis of hypothermia fatalities is often complex due to the absence of pathognomonic lesions and biomarkers. In this study, potential novel biomarkers of hypothermia fatalities were searched in the vitreous humor of known cases of hypothermia fatalities ( = 20) compared to control cases ( = 16), using a targeted metabolomics approach allowing quantitative detection of 188 metabolites. A robust discriminant model with good predictivity was obtained with the supervised OPLS-DA multivariate analysis, showing a distinct separation between the hypothermia and control groups. This signature was characterized by the decreased concentrations of five metabolites (methionine sulfoxide, tryptophan, phenylalanine, alanine, and ornithine) and the increased concentration of 28 metabolites (21 phosphatidylcholines, 3 sphingomyelins, spermine, citrulline, acetylcarnitine, and hydroxybutyrylcarnitine) in hypothermia fatalities compared to controls. The signature shows similarities with already identified features in serum such as the altered concentrations of tryptophan, acylcarnitines, and unsaturated phosphatidylcholines, revealing a highly significant increased activity of methionine sulfoxide reductase, attested by a low methionine sulfoxide-to-methionine ratio. Our results show a preliminary metabolomics signature of hypothermia fatalities in the vitreous humor, highlighting an increased methionine sulfoxide reductase activity.
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http://dx.doi.org/10.1021/acs.jproteome.0c00901DOI Listing
May 2021

LPS-enriched small extracellular vesicles from metabolic syndrome patients trigger endothelial dysfunction by activation of TLR4.

Metabolism 2021 05 11;118:154727. Epub 2021 Feb 11.

SOPAM, U1063, INSERM, UNIV Angers, SFR ICAT, Angers, France; Centre Hospitalo-Universitaire d'Angers, France. Electronic address:

Background: Metabolic syndrome (MetS) is characterized by a cluster of interconnected risk factors -hyperglycemia, dyslipidemia, hypertension and obesity- leading to an increased risk of cardiovascular events. Small extracellular vesicles (sEVs) can be considered as new biomarkers of different pathologies, and they are involved in intercellular communication. Here, we hypothesize that sEVs are implicated in MetS-associated endothelial dysfunction.

Methods: Circulating sEVs of non-MetS (nMetS) subjects and MetS patients were isolated from plasma and characterized. Thereafter, sEV effects on endothelial function were analyzed by measuring nitric oxide (NO) and reactive oxygen species (ROS) production, and mitochondrial dynamic proteins on human endothelial aortic cells (HAoECs).

Results: Circulating levels of sEVs positively correlated with anthropometric and biochemical parameters including visceral obesity, glycaemia, insulinemia, and dyslipidemia. Treatment of HAoECs with sEVs from MetS patients decreased NO production through the inhibition of the endothelial NO-synthase activity. Injection of MetS-sEVs into mice impaired endothelium-dependent relaxation induced by acetylcholine. Furthermore, MetS-sEVs increased DHE and MitoSox-associated fluorescence in HAoECs, reflecting enhanced cytosolic and mitochondrial ROS production which was not associated with mitochondrial biogenesis or dynamic changes. MetS patients displayed elevated circulating levels of LPS in plasma, and, at least in part, it was associated to circulating sEVs. Pharmacological inhibition and down-regulation of TLR4, as well as sEV-carried LPS neutralization, results in a substantial decrease of ROS production induced by MetS-sEVs.

Conclusion: These results evidence sEVs from MetS patients as potential new biomarkers for this syndrome, and TLR4 pathway activation by sEVs provides a link between the endothelial dysfunction and metabolic disturbances described in MetS.
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http://dx.doi.org/10.1016/j.metabol.2021.154727DOI Listing
May 2021

A plasma metabolomic signature of Leber hereditary optic neuropathy showing taurine and nicotinamide deficiencies.

Hum Mol Genet 2021 03;30(1):21-29

Unité Mixte de Recherche (UMR) MITOVASC, Centre National de la Recherche Scientifique (CNRS) 6015, Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, Université d'Angers, 49933 Angers, France.

Leber's hereditary optic neuropathy (LHON) is the most common disorder due to mitochondrial DNA mutations and complex I deficiency. It is characterized by an acute vision loss, generally in young adults, with a higher penetrance in males. How complex I dysfunction induces the peculiar LHON clinical presentation remains an unanswered question. To gain an insight into this question, we carried out a non-targeted metabolomic investigation using the plasma of 18 LHON patients, during the chronic phase of the disease, comparing them to 18 healthy controls. A total of 500 metabolites were screened of which 156 were accurately detected. A supervised Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) highlighted a robust model for disease prediction with a Q2 (cum) of 55.5%, with a reliable performance during the permutation test (cross-validation analysis of variance, P-value = 5.02284e-05) and a good prediction of a test set (P = 0.05). This model highlighted 10 metabolites with variable importance in the projection (VIP) > 0.8. Univariate analyses revealed nine discriminating metabolites, six of which were the same as those found in the Orthogonal Projections to Latent Structures Discriminant Analysis model. In total, the 13 discriminating metabolites identified underlining dietary metabolites (nicotinamide, taurine, choline, 1-methylhistidine and hippurate), mitochondrial energetic substrates (acetoacetate, glutamate and fumarate) and purine metabolism (inosine). The decreased concentration of taurine and nicotinamide (vitamin B3) suggest interesting therapeutic targets, given their neuroprotective roles that have already been demonstrated for retinal ganglion cells. Our results show a reliable predictive metabolomic signature in the plasma of LHON patients and highlighted taurine and nicotinamide deficiencies.
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http://dx.doi.org/10.1093/hmg/ddab013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033144PMC
March 2021

Large Extracellular Vesicle-Associated Rap1 Accumulates in Atherosclerotic Plaques, Correlates With Vascular Risks and Is Involved in Atherosclerosis.

Circ Res 2020 08 16;127(6):747-760. Epub 2020 Jun 16.

From the SOPAM, U1063, INSERM, UNIV Angers, SFR ICAT, France (L.P., X.V.-G., R.S., L.V., L.D., S.L.L., A.V., G.S., S.D., F.G., R.A., M.C.M.).

Rationale: Metabolic syndrome (MetS) is a cluster of interrelated risk factors for cardiovascular diseases and atherosclerosis. Circulating levels of large extracellular vesicles (lEVs), submicrometer-sized vesicles released from plasma membrane, from MetS patients were shown to induce endothelial dysfunction, but their role in early stage of atherosclerosis and on vascular smooth muscle cells (SMC) remain to be fully elucidated.

Objective: To determine the mechanisms by which lEVs lead to the progression of atherosclerosis in the setting of MetS.

Methods And Results: Proteomic analysis revealed that the small GTPase, Rap1 was overexpressed in lEVs from MetS patients compared with those from non-MetS subjects. Rap1 was in GTP-associated active state in both types of lEVs, and Rap1-lEVs levels correlated with increased cardiovascular risks, including stenosis. MetS-lEVs, but not non-MetS-lEVs, increased Rap1-dependent endothelial cell permeability. MetS-lEVs significantly promoted migration and proliferation of human aortic SMC and increased expression of proinflammatory molecules and activation of ERK (extracellular signal-regulated kinase) 5/p38 pathways. Neutralization of Rap1 by specific antibody or pharmacological inhibition of Rap1 completely prevented the effects of lEVs from MetS patients. High-fat diet-fed ApoE mice displayed an increased expression of Rap1 both in aortas and circulating lEVs. lEVs accumulated in plaque atherosclerotic lesions depending on the progression of atherosclerosis. lEVs from high-fat diet-fed ApoE mice, but not those from mice fed with a standard diet, enhanced SMC proliferation. Human atherosclerotic lesions were enriched in lEVs expressing Rap1.

Conclusions: These data demonstrate that Rap1 carried by MetS-lEVs participates in the enhanced SMC proliferation, migration, proinflammatory profile, and activation of ERK5/p38 pathways leading to vascular inflammation and remodeling, and atherosclerosis. These results highlight that Rap1 carried by MetS-lEVs may be a novel determinant of diagnostic value for cardiometabolic risk factors and suggest Rap1 as a promising therapeutic target against the development of atherosclerosis. Graphical Abstract: A graphical abstract is available for this article.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992112PMC
August 2020

Metabolomic Profiling of Plasma and Erythrocytes in Sickle Mice Points to Altered Nociceptive Pathways.

Cells 2020 05 26;9(6). Epub 2020 May 26.

Département de Biochimie et Génétique, Centre Hospitalier Universitaire, 49933 Angers, France.

Few data-driven metabolomic approaches have been reported in sickle cell disease (SCD) to date. We performed a metabo-lipidomic study on the plasma and red blood cells of a steady-state mouse model carrying the homozygous human hemoglobin SS, compared with AS and AA genotypes. Among the 188 metabolites analyzed by a targeted quantitative metabolomic approach, 153 and 129 metabolites were accurately measured in the plasma and red blood cells, respectively. Unsupervised PCAs (principal component analyses) gave good spontaneous discrimination between HbSS and controls, and supervised OPLS-DAs (orthogonal partial least squares-discriminant analyses) provided highly discriminant models. These models confirmed the well-known deregulation of nitric oxide synthesis in the HbSS genotype, involving arginine deficiency and increased levels of dimethylarginines, ornithine, and polyamines. Other discriminant metabolites were newly evidenced, such as hexoses, alpha-aminoadipate, serotonin, kynurenine, and amino acids, pointing to a glycolytic shift and to the alteration of metabolites known to be involved in nociceptive pathways. Sharp remodeling of lysophosphatidylcholines, phosphatidylcholines, and sphingomyelins was evidenced in red blood cells. Our metabolomic study provides an overview of the metabolic remodeling induced by the sickle genotype in the plasma and red blood cells, revealing a biological fingerprint of altered nitric oxide, bioenergetics and nociceptive pathways.
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http://dx.doi.org/10.3390/cells9061334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349104PMC
May 2020

Sexual Dimorphism of Metabolomic Profile in Arterial Hypertension.

Sci Rep 2020 05 5;10(1):7517. Epub 2020 May 5.

Departement de Biochimie et Génétique, Centre Hospitalier Universitaire, Angers, France.

Metabolomic studies have demonstrated the existence of biological signatures in blood of patients with arterial hypertension, but no study has hitherto reported the sexual dimorphism of these signatures. We compared the plasma metabolomic profiles of 28 individuals (13 women and 15 men) with essential arterial hypertension with those of a healthy control group (18 women and 18 men), using targeted metabolomics. Among the 188 metabolites explored, 152 were accurately measured. Supervised OPLS-DA (orthogonal partial least squares-discriminant analysis) showed good predictive performance for hypertension in both sexes (Qcum = 0.59 in women and 0.60 in men) with low risk of overfitting (p-value-CV ANOVA = 0.004 in women and men). Seventy-five and 65 discriminant metabolites with a VIP (variable importance for the projection) greater than 1 were evidenced in women and men, respectively. Both sexes showed a considerable increase in phosphatidylcholines, a decrease in C16:0 with an increase in C28:1 lysophosphatidylcholines, an increase in sphingomyelins, as well as an increase of symmetric dimethylarginine (SDMA), acetyl-ornithine and hydroxyproline. Twenty-nine metabolites, involved in phospholipidic and cardiac remodeling, arginine/nitric oxide pathway and antihypertensive and insulin resistance mechanisms, discriminated the metabolic sexual dimorphism of hypertension. Our results highlight the importance of sexual dimorphism in arterial hypertension.
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http://dx.doi.org/10.1038/s41598-020-64329-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200712PMC
May 2020

Sickle Cell Disease: Metabolomic Profiles of Vaso-Occlusive Crisis in Plasma and Erythrocytes.

J Clin Med 2020 Apr 11;9(4). Epub 2020 Apr 11.

Département de Biochimie et Génétique, Centre Hospitalier Universitaire, 49933 Angers, France.

The metabolomic profile of vaso-occlusive crisis, compared to the basal state of sickle cell disease, has never been reported to our knowledge. Using a standardized targeted metabolomic approach, performed on plasma and erythrocyte fractions, we compared these two states of the disease in the same group of 40 patients. Among the 188 metabolites analyzed, 153 were accurately measured in plasma and 143 in red blood cells. Supervised paired partial least squares discriminant analysis (pPLS-DA) showed good predictive performance for test sets with median area under the receiver operating characteristic (AUROC) curves of 99% and mean p-values of 0.0005 and 0.0002 in plasma and erythrocytes, respectively. A total of 63 metabolites allowed discrimination between the two groups in the plasma, whereas 61 allowed discrimination in the erythrocytes. Overall, this signature points to altered arginine and nitric oxide metabolism, pain pathophysiology, hypoxia and energetic crisis, and membrane remodeling of red blood cells. It also revealed the alteration of metabolite concentrations that had not been previously associated with sickle cell disease. Our results demonstrate that the vaso-occlusive crisis has a specific metabolomic signature, distinct from that observed at steady state, which may be potentially helpful for finding predictive biomarkers for this acute life-threatening episode.
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http://dx.doi.org/10.3390/jcm9041092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230294PMC
April 2020

Metabolomics hallmarks OPA1 variants correlating with their in vitro phenotype and predicting clinical severity.

Hum Mol Genet 2020 05;29(8):1319-1329

Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy.

Interpretation of variants of uncertain significance is an actual major challenge. We addressed this question on a set of OPA1 missense variants responsible for variable severity of neurological impairments. We used targeted metabolomics to explore the different signatures of OPA1 variants expressed in Opa1 deleted mouse embryonic fibroblasts (Opa1-/- MEFs), grown under selective conditions. Multivariate analyses of data discriminated Opa1+/+ from Opa1-/- MEFs metabolic signatures and classified OPA1 variants according to their in vitro severity. Indeed, the mild p.I382M hypomorphic variant was segregating close to the wild-type allele, while the most severe p.R445H variant was close to Opa1-/- MEFs, and the p.D603H and p.G439V alleles, responsible for isolated and syndromic presentations, respectively, were intermediary between the p.I382M and the p.R445H variants. The most discriminant metabolic features were hydroxyproline, the spermine/spermidine ratio, amino acid pool and several phospholipids, emphasizing proteostasis, endoplasmic reticulum (ER) stress and phospholipid remodeling as the main mechanisms ranking OPA1 allele impacts on metabolism. These results demonstrate the high resolving power of metabolomics in hierarchizing OPA1 missense mutations by their in vitro severity, fitting clinical expressivity. This suggests that our methodological approach can be used to discriminate the pathological significance of variants in genes responsible for other rare metabolic diseases and may be instrumental to select possible compounds eligible for supplementation treatment.
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http://dx.doi.org/10.1093/hmg/ddaa047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254852PMC
May 2020

A Plasma Metabolomic Profiling of Exudative Age-Related Macular Degeneration Showing Carnosine and Mitochondrial Deficiencies.

J Clin Med 2020 Feb 27;9(3). Epub 2020 Feb 27.

Département de Biochimie et Génétique, Centre Hospitalier Universitaire, 49933 Angers, France .

To determine the plasma metabolomic profile of exudative age-related macular degeneration (AMD), we performed a targeted metabolomics study on the plasma from patients ( = 40, mean age = 81.1) compared to an age- and sex-matched control group ( = 40, mean age = 81.8). All included patients had documented exudative AMD, causing significant visual loss (mean logMAR visual acuity = 0.63), compared to the control group. Patients and controls did not differ in terms of body mass index and co-morbidities. Among the 188 metabolites analyzed, 150 (79.8%) were accurately measured. The concentrations of 18 metabolites were significantly modified in the AMD group, but only six of them remained significantly different after Benjamini-Hochberg correction. Valine, lysine, carnitine, valerylcarnitine and proline were increased, while carnosine, a dipeptide disclosing anti-oxidant and anti-glycating properties, was, on average, reduced by 50% in AMD compared to controls. Moreover, carnosine was undetectable for 49% of AMD patients compared to 18% in the control group (-value = 0.0035). Carnitine is involved in the transfer of fatty acids within the mitochondria; proline, lysine and valerylcarnitine are substrates for mitochondrial electrons transferring flavoproteins, and proline is one of the main metabolites supplying energy to the retina. Overall, our results reveal six new metabolites involved in the plasma metabolomic profile of exudative AMD, suggesting mitochondrial energetic impairments and carnosine deficiency.
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http://dx.doi.org/10.3390/jcm9030631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141125PMC
February 2020

[Multiparametric biochemical analysis revealing an increase of homocysteinemia and NT-proBNP in hypertensive patients living in Bamako (Mali)].

Pan Afr Med J 2020 13;35:10. Epub 2020 Jan 13.

Faculté de Pharmacie, Université des Sciences, des Techniques et des Technologies de Bamako, Mali.

Introduction: Arterial hypertension is a major public health problem in sub-Saharan Africa due to its high frequency and to the cardiovascular risk that it entails. The purpose of this study was to assess the prevalence of clinical and biological risk factors of hypertension in Bamako (Mali).

Methods: We conducted a case-control study, stratified in function of the sex, of 72 participants including 36 patients with hypertension and 36 controls. Twenty-two plasma biochemical parameters have been measured and analyzed using univariate and multivariate tests.

Results: Hyperhomocysteinemia was found in 55.6% of women (p = 0.03) and 100% of men (p = 0.007) with hypertension. High NT-proBNP was also found in 16.7% of women (VIP > 1 in multivariate model) and of men with hypertension (p = 0.00006). A good multivariate predictive model (OPLS-DA) was only obtained in women with high blood pressure, with Qcum = 0.73, attesting severe sexual dimorphism associated with arterial hypertension. This model involved eight parameters whose plasma concentration was modified (homocysteine, NT-proBNP, potassium, urea, blood glucose, sodium, chlorine and total proteins).

Conclusion: We registered a significant association between hyperhomocysteinemia and arterial hypertension. Therefore, the assay of homocysteine associated with good management would decrease the risk of cardiovascular diseases while improving the quality of life of hypertensive patients.
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http://dx.doi.org/10.11604/pamj.2020.35.10.18821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026517PMC
March 2020

A Data Mining Metabolomics Exploration of Glaucoma.

Metabolites 2020 Jan 28;10(2). Epub 2020 Jan 28.

Faculté de santé, Institut MITOVASC, UMR CNRS 6015, INSERM U1083, Université d'Angers, 49933 Angers, France.

Glaucoma is an age related disease characterized by the progressive loss of retinal ganglion cells, which are the neurons that transduce the visual information from the retina to the brain. It is the leading cause of irreversible blindness worldwide. To gain further insights into primary open-angle glaucoma (POAG) pathophysiology, we performed a non-targeted metabolomics analysis on the plasma from POAG patients ( = 34) and age- and sex-matched controls ( = 30). We investigated the differential signature of POAG plasma compared to controls, using liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS). A data mining strategy, combining a filtering method with threshold criterion, a wrapper method with iterative selection, and an embedded method with penalization constraint, was used. These strategies are most often used separately in metabolomics studies, with each of them having their own limitations. We opted for a synergistic approach as a mean to unravel the most relevant metabolomics signature. We identified a set of nine metabolites, namely: nicotinamide, hypoxanthine, xanthine, and 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline with decreased concentrations and N-acetyl-L-Leucine, arginine, RAC-glycerol 1-myristate, 1-oleoyl-RAC-glycerol, cystathionine with increased concentrations in POAG; the modification of nicotinamide, N-acetyl-L-Leucine, and arginine concentrations being the most discriminant. Our findings open up therapeutic perspectives for the diagnosis and treatment of POAG.
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http://dx.doi.org/10.3390/metabo10020049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074047PMC
January 2020

Tryptophane-kynurenine pathway in the remote ischemic conditioning mechanism.

Basic Res Cardiol 2020 01 10;115(2):13. Epub 2020 Jan 10.

Institut Mitovasc, UMR CNRS 6015, INSERM U1083, CHU d'Angers, Université d'Angers, Angers, France.

The actual protective mechanisms underlying cardioprotection with remote ischemic conditioning (RIC) remain unclear. Recent data suggest that RIC induces kynurenine (KYN) and kynurenic acid synthesis, two metabolites derived from tryptophan (TRP), yet a causal relation between TRP pathway and RIC remains to be established. We sought to study the impact of RIC on the levels of TRP and its main metabolites within tissues, and to assess whether blocking kynurenine (KYN) synthesis from TRP would inhibit RIC-induced cardioprotection. In rats exposed to 40-min coronary occlusion and 2-h reperfusion, infarct size was significantly smaller in RIC-treated animals (35.7 ± 3.0% vs. 46.5 ± 2.2%, p = 0.01). This protection was lost in rats that received 1-methyl-tryptophan (1-MT) pretreatment, an inhibitor of KYN synthesis from TRP (infarct size = 46.2 ± 5.0%). Levels of TRP and nine compounds spanning its metabolism through the serotonin and KYN pathways were measured by reversed-phase liquid chromatography-tandem mass spectrometry in the liver, heart, and limb skeletal muscle, either exposed or not to RIC. In the liver, RIC induced a significant increase in xanthurenic acid, nicotinic acid, and TRP. Likewise, RIC increased NAD-dependent deacetylase sirtuin activity in the liver. Pretreatment with 1-MT suppressed the RIC-induced increases in NAD-dependent deacetylase sirtuin activity. Altogether, these findings indicate that RIC mechanism is dependent on TRP-KYN pathway activation.
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http://dx.doi.org/10.1007/s00395-019-0770-xDOI Listing
January 2020

Metabolomics reveals highly regional specificity of cerebral sexual dimorphism in mice.

Prog Neurobiol 2020 01 23;184:101698. Epub 2019 Sep 23.

Département de Biochimie et Génétique, Centre Hospitalier Universitaire d'Angers, France; Equipe Mitolab, Unité Mixte de Recherche MITOVASC, CNRS 6015, INSERM U1083, Université d'Angers, Angers, France. Electronic address:

The development of personalized medicine according to gender calls for the integration of sexual dimorphism in pre-clinical models of diseases. Although sexual dimorphism in the brain of the mouse has been the subject of several behavioral, neuroimaging and experimental studies, very few have characterized the bases of sexual dimorphism in the brain on the omics scale. In particular, physiological variations in metabolomic and lipidomic terms related to gender have not been mapped in the brain. We carried out a metabolomic analysis, targeting 188 metabolites representative of various cellular structures and metabolisms, in three brain regions: frontal cortex, brain stem and cerebellum, in 3-month-old C57BL-6 J male (n = 20) vs. female (n = 20) mice. Our results demonstrate the existence of sexual dimorphism in the whole brain as well as in separate brain regions. Half of the 129 accurately measured metabolites were involved in the sexual dimorphism of the murine brain, but only 8% of those (hydroxyproline, creatinine, hexoses, tryptophan, threonine and lysoPC.a.C18.2) were involved in common in the three cerebral regions, while 71%, including phosphatidylcholines, lysophosphatidylcholines, sphingomyelins, acylcarnitines, amino acids, biogenic amines, and polyamines, were specific to only one region of the brain, underscoring the highly regional specificity of cerebral sexual dimorphism in mice.
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http://dx.doi.org/10.1016/j.pneurobio.2019.101698DOI Listing
January 2020

Plasma homocysteine concentration in privately owned healthy adult cats: assessment of biological determinants and establishment of a reference interval.

J Feline Med Surg 2020 07 19;22(7):623-630. Epub 2019 Aug 19.

Nutrition, Physiopathology and Pharmacology Unit, Oniris - Nantes Atlantic National College of Veterinary Medicine, Food Science and Engineering, Nantes, France.

Objectives: The assessment of homocysteine status in diseased cats has indicated high plasma concentrations in chronic kidney disease and yielded conflicting results with respect to cardiovascular disorders. Previous investigations in small populations of normal cats revealed greater-than-expected variability in plasma homocysteine concentration. The purpose of this study was to determine biological determinants and the reference interval (RI) of plasma homocysteine concentration in the feline species, under strict pre-analytical conditions.

Methods: In this prospective observational study, privately owned healthy adult cats underwent a complete physical examination, urinalysis and blood testing, in order to rule out any signs of disease. Plasma homocysteine concentration was measured using high-performance liquid chromatography-tandem mass spectrometry.

Results: Of 151 cats recruited, 30 cats were not included owing to abnormal physical examination or fractious behaviour, and 30 cats were excluded based on abnormalities on blood work or urinalysis. Plasma homocysteine concentrations >28 µmol/l were associated with a dietary protein content >9.3 g/100 kcal metabolisable energy. The RI for plasma homocysteine concentration was determined to be 6.2-52.3 µmol/l.

Conclusions And Relevance: Normal values for plasma homocysteine concentration in cats have a wide RI, suggesting high inter-individual variability. Whether some healthy cats exhibit impaired homocysteine metabolism remains to be elucidated.
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http://dx.doi.org/10.1177/1098612X19868549DOI Listing
July 2020

Lipidomics Reveals Triacylglycerol Accumulation Due to Impaired Fatty Acid Flux in Opa1-Disrupted Fibroblasts.

J Proteome Res 2019 07 14;18(7):2779-2790. Epub 2019 Jun 14.

Equipe Mitolab, Institut MITOVASC, CNRS 6015, INSERM U1083 , Université d'Angers , 49933 Angers , France.

OPA1 is a dynamin GTPase implicated in mitochondrial membrane fusion. Despite its involvement in lipid remodeling, the function of OPA1 has never been analyzed by whole-cell lipidomics. We used a nontargeted, reversed-phase lipidomics approach, validated for cell cultures, to investigate OPA1-inactivated mouse embryonic fibroblasts ( Opa1 MEFs). This led to the identification of a wide range of 14 different lipid subclasses comprising 212 accurately detected lipids. Multivariate and univariate statistical analyses were then carried out to assess the differences between the Opa1 and Opa1 genotypes. Of the 212 lipids identified, 69 were found to discriminate between Opa1 MEFs and Opa1 MEFs. Among these lipids, 34 were triglycerides, all of which were at higher levels in Opa1 MEFs with fold changes ranging from 3.60 to 17.93. Cell imaging with labeled fatty acids revealed a sharp alteration of the fatty acid flux with a reduced mitochondrial uptake. The other 35 discriminating lipids included phosphatidylcholines, lysophosphatidylcholines, phosphatidylethanolamine, and sphingomyelins, mainly involved in membrane remodeling, and ceramides, gangliosides, and phosphatidylinositols, mainly involved in apoptotic cell signaling. Our results show that the inactivation of OPA1 severely affects the mitochondrial uptake of fatty acids and lipids through membrane remodeling and apoptotic cell signaling.
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http://dx.doi.org/10.1021/acs.jproteome.9b00081DOI Listing
July 2019

Nicotinamide Deficiency in Primary Open-Angle Glaucoma.

Invest Ophthalmol Vis Sci 2019 06;60(7):2509-2514

Equipe Mitolab, Unité Mixte de Recherche MITOVASC, CNRS 6015, INSERM U1083, Université d'Angers, Angers, France.

Purpose: To investigate the plasma concentration of nicotinamide in primary open-angle glaucoma (POAG).

Methods: Plasma of 34 POAG individuals was compared to that of 30 age- and sex-matched controls using a semiquantitative method based on liquid chromatography coupled to high-resolution mass spectrometry. Subsequently, an independent quantitative method, based on liquid chromatography coupled to mass spectrometry, was used to assess nicotinamide concentration in the plasma from the same initial cohort and from a replicative cohort of 20 POAG individuals and 15 controls.

Results: Using the semiquantitative method, the plasma nicotinamide concentration was significantly lower in the initial cohort of POAG individuals compared to controls and further confirmed in the same cohort, using the targeted quantitative method, with mean concentrations of 0.14 μM (median: 0.12 μM; range, 0.06-0.28 μM) in the POAG group (-30%; P = 0.022) and 0.19 μM (median: 0.18 μM; range, 0.08-0.47 μM) in the control group. The quantitative dosage also disclosed a significantly lower plasma nicotinamide concentration (-33%; P = 0.011) in the replicative cohort with mean concentrations of 0.14 μM (median: 0.14 μM; range, 0.09-0.25 μM) in the POAG group, and 0.19 μM (median: 0.21 μM; range, 0.09-0.26 μM) in the control group.

Conclusions: Glaucoma is associated with lower plasmatic nicotinamide levels, compared to controls, suggesting that nicotinamide supplementation might become a future therapeutic strategy. Further studies are needed, in larger cohorts, to confirm these preliminary findings.
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http://dx.doi.org/10.1167/iovs.19-27099DOI Listing
June 2019

The Metabolomic Signature of Opa1 Deficiency in Rat Primary Cortical Neurons Shows Aspartate/Glutamate Depletion and Phospholipids Remodeling.

Sci Rep 2019 04 15;9(1):6107. Epub 2019 Apr 15.

Equipe Mitolab, Institut MITOVASC, CNRS 6015, INSERM U1083, Université d'Angers, Angers, France.

Pathogenic variants of OPA1, which encodes a dynamin GTPase involved in mitochondrial fusion, are responsible for a spectrum of neurological disorders sharing optic nerve atrophy and visual impairment. To gain insight on OPA1 neuronal specificity, we performed targeted metabolomics on rat cortical neurons with OPA1 expression inhibited by RNA interference. Of the 103 metabolites accurately measured, univariate analysis including the Benjamini-Hochberg correction revealed 6 significantly different metabolites in OPA1 down-regulated neurons, with aspartate being the most significant (p < 0.001). Supervised multivariate analysis by OPLS-DA yielded a model with good predictive capability (Q = 0.65) and a low risk of over-fitting (permQ2 = -0.16, CV-ANOVA p-value 0.036). Amongst the 46 metabolites contributing the most to the metabolic signature were aspartate, glutamate and threonine, which all decreased in OPA1 down-regulated neurons, and lysine, 4 sphingomyelins, 4 lysophosphatidylcholines and 32 phosphatidylcholines which were increased. The phospholipid signature may reflect intracellular membrane remodeling due to loss of mitochondrial fusion and/or lipid droplet accumulation. Aspartate and glutamate deficiency, also found in the plasma of OPA1 patients, is likely the consequence of respiratory chain deficiency, whereas the glutamate decrease could contribute to the synaptic dysfunction that we previously identified in this model.
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http://dx.doi.org/10.1038/s41598-019-42554-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465244PMC
April 2019

Metabolomic Profiling of Aqueous Humor in Glaucoma Points to Taurine and Spermine Deficiency: Findings from the Eye-D Study.

J Proteome Res 2019 03 11;18(3):1307-1315. Epub 2019 Feb 11.

Unité Mixte de Recherche MITOVASC, équipe Mitolab, Centre National de la Recherche Scientifique 6015, Institut National de la Santé et de la Recherche Médicale U1083 , Université d'Angers , Angers 49035 , France.

We compared the metabolomic profile of aqueous humor from patients with primary open-angle glaucoma (POAG; n = 26) with that of a group of age- and sex-matched non-POAG controls (n = 26), all participants undergoing cataract surgery. Supervised paired partial least-squares discriminant analysis showed good predictive performance for test sets with a median area under the receiver operating characteristic of 0.89 and a p-value of 0.0087. Twenty-three metabolites allowed discrimination between the two groups. Univariate analysis after the Benjamini-Hochberg correction showed significant differences for 13 of these metabolites. The POAG metabolomic signature indicated reduced concentrations of taurine and spermine and increased concentrations of creatinine, carnitine, three short-chain acylcarnitines, 7 amino acids (glutamine, glycine, alanine, leucine, isoleucine, hydroxyl-proline, and acetyl-ornithine), 7 phosphatidylcholines, one lysophosphatidylcholine, and one sphingomyelin. This suggests an alteration of metabolites involved in osmoprotection (taurine and creatinine), neuroprotection (spermine, taurine, and carnitine), amino acid metabolism (7 amino acids and three acylcarnitines), and the remodeling of cell membranes drained by the aqueous humor (hydroxyproline and phospholipids). Five of these metabolic alterations, already reported in POAG plasma, concern spermine, C3 and C4 acylcarnitines, PC aa 34:2, and PC aa 36:4, thus highlighting their importance in the pathogenesis of glaucoma.
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http://dx.doi.org/10.1021/acs.jproteome.8b00915DOI Listing
March 2019

Metabolomics signatures of a subset of RET variants according to their oncogenic risk level.

Endocr Relat Cancer 2019 03;26(3):379-389

Département de Biochimie et Génétique, CHU d'Angers, Angers, France.

Thirty percent of medullary thyroid carcinomas (MTCs) are related to dominant germline pathogenic variants in the RET proto-oncogene. According to their aggressiveness, these pathogenic variants are classified in three risk levels: 'moderate', 'high' and 'highest'. The present study compares the metabolomics profiles of five pathogenic variants, whether already classified or not. We have generated six stable murine fibroblast cell lines (NIH3T3) expressing the WT allele or variants of the human RET gene, with different levels of pathogenicity, including the M918V variant that is yet to be accurately classified. We carried out a targeted metabolomics study of the cell extracts with a QTRAP mass spectrometer, using the Biocrates Absolute IDQ p180 kit, which allows the quantification of 188 endogenous molecules. The data were then subjected to multivariate statistical analysis. One hundred seventy three metabolites were accurately measured. The metabolic profiles of the cells expressing the RET variants were found to be correlated with their oncogenic risk. In addition, the statistical model we constructed for predicting the oncogenic risk attributed a moderate risk to the M918V variant. Our results indicate that metabolomics may be useful for characterizing the pathogenicity of the RET gene variants and their levels of aggressiveness.
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http://dx.doi.org/10.1530/ERC-18-0314DOI Listing
March 2019

Alagille syndrome: a case report.

Ann Biol Clin (Paris) 2018 Dec;76(6):675-680

Département de biochimie et génétique, CHU Angers, France.

We report the case of an infant hospitalized for neonatal anoxic ischemia in whom the diagnosis of Alagille syndrome (SAG ; MIM # 118450) was suspected in the presence of major cholestasis, cardiac malformations, suggestive facial dysmorphia, and vertebral and ocular abnormalities. This diagnosis was later confirmed by the detection of a heterozygous pathogenic variant in the gene JAG1, i.e. the gene predominantly responsible for this syndrome with autosomal dominant transmission, which affects about 1 in 30 000 births. The purpose of this presentation is to highlight this relatively unknown syndrome, both from the diagnostic and physiopathological points of view. This clinical case is also an opportunity to discuss pseudo-bisalbuminemia, accidentally discovered in the patient during the exploration of serum proteins by capillary electrophoresis. In total, the medical biologist is directly concerned by the multidisciplinary management of this syndrome, which involves biological perturbances in multiple organs.
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http://dx.doi.org/10.1684/abc.2018.1399DOI Listing
December 2018

Phenotyping of circulating extracellular vesicles (EVs) in obesity identifies large EVs as functional conveyors of Macrophage Migration Inhibitory Factor.

Mol Metab 2018 12 9;18:134-142. Epub 2018 Oct 9.

INSERM U1063, Oxidative Stress and Metabolic Pathologies, Angers University, France. Electronic address:

Objective: Obesity-associated metabolic dysfunctions are linked to dysregulated production of adipokines. Accumulating evidence suggests a role for fat-derived extracellular vesicles (EVs) in obesity-metabolic disturbances. Since EVs convey numerous proteins we aimed to evaluate their contribution in adipokine secretion.

Methods: Plasma collected from metabolic syndrome patients were used to isolate EV subtypes, namely microvesicles (MVs) and exosomes (EXOs). Numerous soluble factor concentrations were measured successively on total, MV- and EXO-depleted plasma by multiplexed immunoassays.

Results: Circulating MVs and EXOs were significantly increased with BMI, supporting a role of EVs as metabolic relays in obesity. Obesity was associated with dysregulated soluble factor production. Sequential depletion of plasma MVs and EXOs did not modify plasma levels of these molecules, with the exception of Macrophage Migration Inhibitory Factor (MIF). Half of plasma MIF circulated within MVs, and this MV secretory pathway was conserved over different MIF-producing cells. Although MV-associated MIF triggered rapid ERK1/2 activation in macrophages, these functional MV-MIF effects specifically relied on MIF tautomerase activity.

Conclusion: Our results emphasize the importance of reconsidering MIF-metabolic actions with regard to its MV-associated form and opening new EV-based strategies for therapeutic MIF approaches.
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http://dx.doi.org/10.1016/j.molmet.2018.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309717PMC
December 2018

A serum metabolomics signature of hypothermia fatalities involving arginase activity, tryptophan content, and phosphatidylcholine saturation.

Int J Legal Med 2019 May 18;133(3):889-898. Epub 2018 Sep 18.

Centre Universitaire Romand de Médecine Légale, Hôpital Universitaire de Lausanne, Chemin de la Vuliette 4, 1000, Lausanne 25, Switzerland.

Introduction: Hypothermia is a potentially lethal condition whose postmortem diagnosis is often complex to perform due to the absence of pathognomonic lesions and biomarkers. Our first study of human serum and urinary metabolome in hypothermia fatalities sought novel biomarkers with better diagnostic performances than those already existing.

Material And Method: Thirty-two cases of hypothermia deaths and 16 cases excluding known antemortem exposure to cold or postmortem elements suggesting hypothermia were selected. A targeted metabolomic study allowing the detection and quantitation of 188 metabolites was performed on collected serum and urine using direct flow injection (FIA) and liquid chromatography (LC) separation, both coupled to tandem mass spectrometry (MS/MS). Amino acid quantification was also carried on using an in-house LC-MS/MS method in order to replicate the results obtained with the metabolomic study.

Results: A discriminant metabolic signature allowing a clear separation between hypothermia and control groups was obtained in the serum. This signature was characterized by increased arginase activity and fatty acid unsaturation along with decreased levels of tryptophan in hypothermia fatalities compared to controls. By contrast, no discriminant metabolic signature separating hypothermia from control fatalities was found in urines.

Discussion: The serum metabolic signature of hypothermia fatalities herein observed pointed toward metabolic adaptations that likely aimed at heat production enhancement, endothelial function, and cell membrane fluidity preservation. Novel biomarkers potentially useful in a hypothermia diagnosis were also identified.
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http://dx.doi.org/10.1007/s00414-018-1937-yDOI Listing
May 2019

A Metabolomics Profiling of Glaucoma Points to Mitochondrial Dysfunction, Senescence, and Polyamines Deficiency.

Invest Ophthalmol Vis Sci 2018 09;59(11):4355-4361

Equipe Mitolab, Institut Mitovasc, Centre National de la Recherche Scientifique 6015, Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, Université d'Angers, Angers, France.

Purpose: To determine the plasma metabolomic signature of primary open-angle glaucoma (POAG).

Methods: We compared the metabolomic profiles of plasma from individuals with POAG (n = 36) with age- and sex-matched controls with cataract (n = 27). A targeted metabolomics study was performed using the standardized p180 Biocrates Absolute IDQ p180 kit with a QTRAP 5500 mass spectrometer. Multivariate analyses were performed using principal component analysis (PCA) and the least absolute shrinkage and selection operator (LASSO) method.

Results: Among the 151 metabolites accurately measured, combined univariate and multivariate analyses revealed 18 discriminant metabolites belonging to the carbohydrate, acyl-carnitine, phosphatidylcholine, amino acids, and polyamine families. The metabolomic signature of POAG points to three closely interdependent pathophysiologic conditions; that is, defective mitochondrial oxidation of energetic substrates, altered metabolism resembling that observed in senescence, and a deficiency in spermidine and spermine, both polyamines being involved in the protection of retinal ganglion cells.

Conclusions: Our results highlight a systemic and age-related mitochondrial defect in the pathogenesis of POAG.
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http://dx.doi.org/10.1167/iovs.18-24938DOI Listing
September 2018

The Metabolomic Bioenergetic Signature of Opa1-Disrupted Mouse Embryonic Fibroblasts Highlights Aspartate Deficiency.

Sci Rep 2018 08 1;8(1):11528. Epub 2018 Aug 1.

Equipe Mitolab, Institut MITOVASC, CNRS 6015, INSERM U1083, Université d'Angers, Angers, France.

OPA1 (Optic Atrophy 1) is a multi-isoform dynamin GTPase involved in the regulation of mitochondrial fusion and organization of the cristae structure of the mitochondrial inner membrane. Pathogenic OPA1 variants lead to a large spectrum of disorders associated with visual impairment due to optic nerve neuropathy. The aim of this study was to investigate the metabolomic consequences of complete OPA1 disruption in Opa1 mouse embryonic fibroblasts (MEFs) compared to their Opa1 counterparts. Our non-targeted metabolomics approach revealed significant modifications of the concentration of several mitochondrial substrates, i.e. a decrease of aspartate, glutamate and α-ketoglutaric acid, and an increase of asparagine, glutamine and adenosine-5'-monophosphate, all related to aspartate metabolism. The signature further highlighted the altered metabolism of nucleotides and NAD together with deficient mitochondrial bioenergetics, reflected by the decrease of creatine/creatine phosphate and pantothenic acid, and the increase in pyruvate and glutathione. Interestingly, we recently reported significant variations of five of these molecules, including aspartate and glutamate, in the plasma of individuals carrying pathogenic OPA1 variants. Our findings show that the disruption of OPA1 leads to a remodelling of bioenergetic pathways with the central role being played by aspartate and related metabolites.
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http://dx.doi.org/10.1038/s41598-018-29972-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070520PMC
August 2018

Extracellular Vesicles: Mechanisms in Human Health and Disease.

Antioxid Redox Signal 2019 02 30;30(6):813-856. Epub 2018 Apr 30.

1 INSERM UMR 1063, Stress Oxydant et Pathologies Métaboliques, UNIV Angers, Université Bretagne Loire, Angers, France.

Significance: Secreted extracellular vesicles (EVs) are now considered veritable entities for diagnosis, prognosis, and therapeutics. These structures are able to interact with target cells and modify their phenotype and function. Recent Advances: Since composition of EVs depends on the cell type of origin and the stimulation that leads to their release, the analysis of EV content remains an important input to understand the potential effects of EVs on target cells.

Critical Issues: Here, we review recent data related to the mechanisms involved in the formation of EVs and the methods allowing specific EV isolation and identification. Also, we analyze the potential use of EVs as biomarkers in different pathologies such as diabetes, obesity, atherosclerosis, neurodegenerative diseases, and cancer. Besides, their role in these diseases is discussed. Finally, we consider EVs enriched in microRNA or drugs as potential therapeutic cargo able to deliver desirable information to target cells/tissues.

Future Directions: We underline the importance of the homogenization of the parameters of isolation of EVs and their characterization, which allow considering EVs as excellent biomarkers for diagnosis and prognosis.
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http://dx.doi.org/10.1089/ars.2017.7265DOI Listing
February 2019

A redox-sensitive signaling pathway mediates pro-angiogenic effect of chlordecone via estrogen receptor activation.

Int J Biochem Cell Biol 2018 04 13;97:83-97. Epub 2018 Feb 13.

INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Université d'Angers, Université Bretagne-Loire, Angers, France; Départment de Biochimie et Génétique, Centre Hospitalier Universitaire, Angers, France. Electronic address:

Aim: Chlordecone is able to induce pro-angiogenic effect through an estrogen receptor (ERα) pathway involving NO release and VEGF. The present study aimed to determine the molecular mechanisms by which chlordecone promotes angiogenesis in human endothelial cells.

Results: High but not low concentration of chlordecone increased mitochondrial respiratory capacity and mitochondrial DNA content in endothelial cells. The ROS scavenger MnTMPyP was able to prevent the increase of both VEGF expression and capillary length induced by chlordecone. A significant increase of cytoplasmic O production was observed after 1 and 4 h incubation of chlordecone, but not after 2 h. The NADPH oxidase inhibitor apocynin or silencing p47phox prevented angiogenesis and tube formation but also the increase in production of O at 1 h. In addition, apocynin as well silencing p47phox prevented eNOS activation and the NO synthase inhibitor L-NAME inhibited mitochondrial Oproduction. All the previous effects of chlordecone were prevented by fulvestrant.

Conclusion: Our results indicate that an adaptation of the mitochondrial energy metabolism occurs in the chlordecone angiogenic response. Finally, we showed that chlordecone induces endothelial cells angiogenesis by a cross-talk involving NADPH oxidase and mitochondrial Ovia a NO sensitive pathways through activation of ERα. These findings propose that a molecular mechanism may partly explain the epidemiological evidence implicating chlordecone as risk factor carcinogenesis.
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http://dx.doi.org/10.1016/j.biocel.2018.02.008DOI Listing
April 2018

A Plasma Metabolomic Signature of the Exfoliation Syndrome Involves Amino Acids, Acylcarnitines, and Polyamines.

Invest Ophthalmol Vis Sci 2018 02;59(2):1025-1032

Equipe Mitolab, Institut MITOVASC, UMR CNRS 6015, INSERM U1083, Université d'Angers, Angers, France.

Purpose: To determine the plasma metabolomic signature of the exfoliative syndrome (XFS), the most common cause worldwide of secondary open-angle glaucoma.

Methods: We performed a targeted metabolomic study, using the standardized p180 Biocrates Absolute IDQ p180 kit with a QTRAP 5500 mass spectrometer, to compare the metabolomic profiles of plasma from individuals with XFS (n = 16), and an age- and sex-matched control group with cataract (n = 18).

Results: A total of 151 metabolites were detected correctly, 16 of which allowed for construction of an OPLS-DA model with a good predictive capability (Q2cum = 0.51) associated with a low risk of over-fitting (permQ2 = -0.48, CV-ANOVA P-value <0.001). The metabolites contributing the most to the signature were octanoyl-carnitine (C8) and decanoyl-carnitine (C10), the branched-chain amino acids (i.e., isoleucine, leucine, and valine), and tyrosine, all of which were at higher concentrations in the XFS group, whereas spermine and spermidine, together with their precursor acetyl-ornithine, were at lower concentrations than in the control group.

Conclusions: We identified a significant metabolomic signature in the plasma of individuals with XFS. Paradoxically, this signature, characterized by lower concentrations of the neuroprotective spermine and spermidine polyamines than in controls, partially overlaps the plasma metabolomic profile associated with insulin resistance, despite the absence of evidence of insulin resistance in XFS.
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http://dx.doi.org/10.1167/iovs.17-23055DOI Listing
February 2018

Maternal protein restriction during lactation induces early and lasting plasma metabolomic and hepatic lipidomic signatures of the offspring in a rodent programming model.

J Nutr Biochem 2018 05 10;55:124-141. Epub 2017 Dec 10.

INRA, UMR1280, Physiopathologie des Adaptations Nutritionnelles, Institut des maladies de l'appareil digestif (IMAD), Centre de Recherche en Nutrition Humaine Ouest (CRNH), Nantes, France; LUNAM, Institut des maladies de l'appareil digestif (IMAD), Centre de Recherche en Nutrition Humaine Ouest (CRNH), Nantes, France. Electronic address:

Perinatal undernutrition affects not only fetal and neonatal growth but also adult health outcome, as suggested by the metabolic imprinting concept. However, the exact mechanisms underlying offspring metabolic adaptations are not yet fully understood. Specifically, it remains unclear whether the gestation or the lactation is the more vulnerable period to modify offspring metabolic flexibility. We investigated in a rodent model of intrauterine growth restriction (IUGR) induced by maternal protein restriction (R) during gestation which time window of maternal undernutrition (gestation, lactation or gestation-lactation) has more impact on the male offspring metabolomics phenotype. Plasma metabolome and hepatic lipidome of offspring were characterized through suckling period and at adulthood using liquid chromatography-high-resolution mass spectrometry. Multivariate analysis of these fingerprints highlighted a persistent metabolomics signature in rats suckled by R dams, with a clear-cut discrimination from offspring fed by control (C) dams. Pups submitted to a nutritional switch at birth presented a metabolomics signature clearly distinct from that of pups nursed by dams maintained on a consistent perinatal diet. Control rats suckled by R dams presented transiently higher branched-chain amino acid (BCAA) oxidation during lactation besides increased fatty acid (FA) β-oxidation, associated with preserved insulin sensitivity and lesser fat accretion that persisted throughout their life. In contrast, IUGR rats displayed permanently impaired β-oxidation, associated to increased glucose or BCAA oxidation at adulthood, depending on the fact that pups experienced slow postnatal or catch-up growth, as suckled by R or C dams, respectively. Taken together, these findings provide evidence for a significant contribution of the lactation period in metabolic programming.
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http://dx.doi.org/10.1016/j.jnutbio.2017.11.009DOI Listing
May 2018

A Plasma Metabolomic Signature Involving Purine Metabolism in Human Optic Atrophy 1 (OPA1)-Related Disorders.

Invest Ophthalmol Vis Sci 2018 01;59(1):185-195

Equipe Mitolab, Institut MITOVASC, Centre National de la Recherche Scientifique 6015, Institut National de la Santé et de la Recherche Médicale U1083, Université d'Angers, Angers, France.

Purpose: Dominant optic atrophy (DOA; MIM [Mendelian Inheritance in Man] 165500), resulting in retinal ganglion cell degeneration, is mainly caused by mutations in the optic atrophy 1 (OPA1) gene, which encodes a dynamin guanosine triphosphate (GTP)ase involved in mitochondrial membrane processing. This work aimed at determining whether plasma from OPA1 pathogenic variant carriers displays a specific metabolic signature.

Methods: We applied a nontargeted clinical metabolomics pipeline based on ultra-high-pressure liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) allowing the exploration of 500 polar metabolites in plasma. We compared the plasma metabolic profiles of 25 patients with various OPA1 pathogenic variants and phenotypes to those of 20 healthy controls. Statistical analyses were performed using univariate and multivariate (principal component analysis [PCA], orthogonal partial least-squares discriminant analysis [OPLS-DA]) methods and a machine learning approach, the Biosigner algorithm.

Results: A robust and relevant predictive model characterizing OPA1 individuals was obtained, based on a complex panel of metabolites with altered concentrations. An impairment of the purine metabolism, including significant differences in xanthine, hypoxanthine, and inosine concentrations, was at the foreground of this signature. In addition, the signature was characterized by differences in urocanate, choline, phosphocholine, glycerate, 1-oleoyl-rac-glycerol, rac-glycerol-1-myristate, aspartate, glutamate, and cystine concentrations.

Conclusions: This first metabolic signature reported in the plasma of patient carrying OPA1 pathogenic variants highlights the unexpected involvement of purine metabolism in the pathophysiology of DOA.
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http://dx.doi.org/10.1167/iovs.17-23027DOI Listing
January 2018
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